Birgit Aigner

Effect of Platelet-Rich Plasma on the Biologic Activity of the Human Rotator-Cuff Fibroblasts: A Controlled In Vitro Study

To assess the in vitro effect of platelet‐rich plasma (PRP) on biological activity of the human rotator cuff fibroblasts and to describe the optimal dose‐response to maximize cellular stimulation while reducing potential risk. Rotator cuff (RC) fibroblasts of n = 6 patients (mean age of 65.2 years) undergoing arthroscopic cuff tear reconstruction were cultured in vitro for 21 days and stimulated with PRP in three different concentrations (1‐, 5‐, and 10‐fold). Samples were obtained for DNA and GAG measurement at 1, 7, 14, and 21 days. The biological outcomes were regressed on the PRP concentration. The application of PRP significantly influenced the fibroblast proliferation and activity of the human rotator cuff with elevated glycosaminoglycan (GAG) and DNA levels. The dosage of PRP had the significantly highest impact on this proliferation using a onefold or fivefold application. PRP has a significant effect on fibroblast proliferation of the human rotator cuff in vitro with an optimal benefit using a onefold or fivefold PRP concentration. This study justifies further in vivo investigations using PRP at the human rotator cuff.

β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis.

Background: IL‐17A is a key driver of human autoimmune diseases, particularly psoriasis. Objective: We sought to determine the role of IL‐17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL‐17A–driven pathology. Methods: We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti–IL‐17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases. Results: IL‐17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P < .001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. &bgr;‐Defensin 2 (BD‐2) was identified as a biomarker of IL‐17A–driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P < .0001; 2747 vs <218 pg/mL in dermis, P < .001), responsiveness to secukinumab therapy, and synergistic induction by IL‐17A and TNF‐&agr; in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL‐17A driven, we found that BD‐2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD‐2 levels correlated well with IL‐17A levels (r = 0.70, n = 199, P < .001) and Psoriasis Area and Severity Index scores (r = 0.53, n = 281, P < .001). Conclusion: IL‐17A is a primary driver of skin pathology in patients with psoriasis, and serum BD‐2 is an easily measurable biomarker of IL‐17A–driven skin pathology.

Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion

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Clinical Overview of Cutaneous Features in Hypereosinophilic Syndrome

The hypereosinophilic syndromes (HES) are a heterogeneous group of disorders defined as persistent and marked blood eosinophilia of unknown origin with systemic organ involvement. HES is a potentially severe multisystem disease associated with considerable morbidity. Skin involvement and cutaneous findings frequently can be seen in those patients. Skin symptoms consist of angioedema; unusual urticarial lesions; and eczematous, therapy-resistant, pruriginous papules and nodules. They may be the only obvious clinical symptoms. Cutaneous features can give an important hint to the diagnosis of this rare and often severe illness. Based on advances in molecular and genetic diagnostic techniques and on increasing experience with characteristic clinical features and prognostic markers, therapy has changed radically. Current therapies include corticosteroids, hydroxyurea, interferon-α, the tyrosine kinase inhibitor imatinib mesylate, and (in progress) the monoclonal anti–interleukin-5 antibodies. This article provides an overview of current concepts of disease classification, different skin findings, and therapy for HES.

Sun-induced Pustular Dermatosis of the Scalp - A New Variant of Erosive Pustular Dermatosis of the Scalp?

© 2014 The Authors. doi: 10.2340/00015555-1723 Journal Compilation

Pseudomonas oryzihabitans cutaneous ulceration from Octopus vulgaris bite: a case report and review of the literature.

BACKGROUND Octopus vulgaris is a common marine animal that can be found in nearly all tropical and semitropical waters around the world. It is a peaceful sea dweller with a parrotlike beak, and its primary defense is to hide through camouflaging adjustments. Bites from animals of the class Cephalopoda are very rare. We describe a boy who was bitten on his forearm by an Octopus vulgaris. OBSERVATION A 9 -year-old boy was bitten by an Octopus vulgaris while snorkeling. There was no strong bleeding or systemic symptoms; however, 2 days later, a cherry-sized, black, ulcerous lesion developed, surrounded by a red circle that did not heal over months and therefore had to be excised. Histologic examination showed ulceration with extensive necrosis of the dermis and the epidermis. A microbial smear revealed Pseudomonas (formerly known as Flavimonas) oryzihabitans. After excision, the wound healed within 2 weeks, without any complications or signs of infection. CONCLUSIONS To the best of our knowledge, this case represents the first report of an Octopus vulgaris bite resulting in an ulcerative lesion with slow wound healing owing to P oryzihabitans infection. We recommend greater vigilance regarding bacterial contamination when treating skin lesions caused by marine animals.

Bioavailability of insulin detemir and human insulin at the level of peripheral interstitial fluid in humans, assessed by open-flow microperfusion

To find an explanation for the lower potency of insulin detemir observed in humans compared with unmodified human insulin by investigating insulin detemir and human insulin concentrations directly at the level of peripheral insulin‐sensitive tissues in humans in vivo.

[Cutaneous sarcomas: update on selected fibrohistiocytic and myofibroblastic tumors].

BACKGROUND Malignant fibrohistiocytic tumors are a heterogeneous group of mesenchymal neoplasms that may occur in the skin and subcutaneous tissues. DIAGNOSIS Diagnosis of these tumors may be difficult, as they are rare, and a wide morphological diversity of types and subtypes has been described. In this update, relevant aspects of selected entities like dermatofibrosarcoma protuberans, desmoid tumor, atypical fibroxanthoma, pleomorphic dermal sarcoma, and myxofibrosarcoma are discussed according to the WHO classification of 2013. The typical clinical feature of these tumors is their mostly asymptomatic appearance. For diagnosis, the histologic workup is therefore the key feature; herein immunohistochemistry as well as molecular diagnostics become increasingly important. THERAPY The primary treatment for locally resectable tumors is complete surgical removal; chemotherapy, radiation, and targeted therapies with kinase inhibitors are available for inoperable and metastatic disease.ZusammenfassungHintergrundMaligne fibrohistiozytäre und myofibrozytäre Tumore stellen eine heterogene Gruppe mesenchymaler Neoplasien dar, die in der Kutis und Subkutis auftreten. DiagnoseDie Diagnose dieser seltenen Tumore wird durch eine ausgeprägte morphologische Vielfalt erschwert. In diesem Update werden relevante Aspekte der ausgewählten Entitäten Dermatofibrosarcoma protuberans, Desmoidtumor, atypisches Fibroxanthom, pleomorphes dermales Sarkom und Myxofibrosarkom entsprechend der WHO-Klassifikation von 2013 diskutiert. Die Klinik dieser Tumore ist oft uncharakteristisch; die histologische Aufarbeitung gilt daher als Goldstandard zur Diagnosesicherung. Hierbei nehmen die Immunhistochemie und die molekulare Diagnostik einen stetig größer werdenden Stellenwert ein. TherapieDie Therapie der Wahl stellt bei lokal behandelbaren Tumoren die komplette chirurgische Exzision dar. Chemotherapie, Radiatio sowie zunehmend auch die zielgerichtete Therapie mit Signaltransduktionsinhibitoren kommen bei inoperablen und fortgeschrittenen Tumoren zur Anwendung.AbstractBackgroundMalignant fibrohistiocytic tumors are a heterogeneous group of mesenchymal neoplasms that may occur in the skin and subcutaneous tissues. DiagnosisDiagnosis of these tumors may be difficult, as they are rare, and a wide morphological diversity of types and subtypes has been described. In this update, relevant aspects of selected entities like dermatofibrosarcoma protuberans, desmoid tumor, atypical fibroxanthoma, pleomorphic dermal sarcoma, and myxofibrosarcoma are discussed according to the WHO classification of 2013. The typical clinical feature of these tumors is their mostly asymptomatic appearance. For diagnosis, the histologic workup is therefore the key feature; herein immunohistochemistry as well as molecular diagnostics become increasingly important. TherapyThe primary treatment for locally resectable tumors is complete surgical removal; chemotherapy, radiation, and targeted therapies with kinase inhibitors are available for inoperable and metastatic disease.

Response of patients with metastatic uveal melanoma to combined treatment with fotemustine and sorafenib

Editor, U veal melanoma is the 2nd most common type of melanoma after cutaneous melanoma. Survival time for unselected stage IV uveal melanoma patients with liver involvement is poor with mean 4–5 months, and there are currently no approved systemic treatments (Augsburger et al. 2009). Fotemustine is a nitrosourea alkylating agent with a high hepatic extraction rate. A phase III study, which was performed on uveal melanoma patients with hepatic metastases, showed an overall survival of 14.6 months for intrahepatic and 13.7 for intravenous fotemustine (Leyvraz et al. 2012). The multikinase inhibitor sorafenib targets both tumour-cell proliferation and angiogenesis. In preclinical studies, sorafenib inhibited growth in conjunctival melanoma cell lines efficiently and was also able to enhance the antitumour activity of chemotherapeutic agents (Heim et al. 2003; Carter et al. 2007). We evaluated retrospectively the benefit of a combination therapy with fotemustine and sorafenib in eight patients with stage IV uveal melanoma referred to our department for systemic therapy in the years 2010–2012. Fotemustine 100 mg/m2 was injected intravenously every 3 weeks after an induction cycle with administration on days 1 and 8. It was combined with sorafenib 400 mg orally twice daily. Array-CGH for genetic aberrations was performed on tumour samples. Survival data were calculated using Kaplan–Meier estimates. The patients were unselected, and six of eight had progressed under previous therapies such as systemic dacarbazine-based chemotherapy, hepatic intra-arterial therapies and histopathologically incomplete removal of liver metastases. The median interval between diagnosis of the primary tumour and the detection of metastases was 30.7 months (range 17.3–183.2); ECOG performance status was 0–1. A total of 25 cycles of fotemustine were administered to our patients. Reasons for discontinuation were disease progression in seven patients and grade III pancytopenia and neutropenic fever in one patient. Haematologic side-effects grade 1–3 made delay of chemotherapy necessary in all our patients, as well as dose reductions in fotemustine to 75% or 50% in two patients. Dose reductions in sorafenib to 400 mg once daily were performed in three patients due to neutropenia and/or thrombocytopenia. Hand–foot syndrome and/or a maculopapular rash were observed in half of our patients leading to sorafenib dose reduction in one patient. One patient’s sorafenib dosage had to be reduced due to an exudative multiforme-like exanthema. Median survival from first detection of metastases was 22.3 months (range 7.1–30.3 months). The 1-year survival rate was 75%. Two patients were still alive at data analysis (Table 1). Median survival time from start of therapy was 15.9 months (range 5.6– 29.6 months). Three of our eight patients showed partial response or stable disease, equalling a disease control rate of 37.5%. The patient who suffered only from lung metastases showed a partial remission. Two patients with liver metastases depicted stable disease up to 13 months. Similar results were observed by Kaempgen et al., who could show a disease control rate of 42.8% for patients with metastatic uveal melanoma treated with the fotemustine i.v. and sorafenib p.o. after they had progressed under treatment with i.a. or i.v. fotemustine (Kaempgen et al. 2012). Tumour tissue of six of our eight patients was analysed and showed a monosomy of chromosome 3 and a gain on chromosome 8q24, associating the tumours with aggressive biological behaviour and poor response to metastatic treatment compared to those with only a partial change in chromosome 3 or chromosome 3 disomy (Abdel-Rahman et al. 2012).

Interleukin-17A blockade with secukinumab results in decreased neutrophil infiltration in psoriasis: minimally-invasive measurement by tape stripping

Psoriasis is a well characterized interleukin (IL)-17A-driven skin disease with neutrophil infiltration and epidermal hyperkeratosis. Several biomarkers, most prominently β-defensin-2 (BD-2), have been identified using local and systemic invasive measurements as responsive markers of IL-17A-driven skin pathology. We sought to determine whether measurements of epidermal proteins by tape stripping could offer a minimally-invasive method to assess treatment responses. We compared the expression of 170 proteins in the epidermis (tape stripping) and dermis (open flow microperfusion) of 8 psoriatic subjects before and after administration of a single dose of subcutaneous (s.c.) antiIL-17A mAb secukinumab. Proteomic analyses of tape strips revealed a >3-fold decrease in 32 epidermal and inflammatory cell proteins in response to secukinumab. The epidermal proteins with the largest (>10-fold) decreases were: matrix metalloproteinase-8 (MMP-8, 15.68-fold, p<0.05); myeloperoxidase (MPO, 14.72-fold, p<0.005); IL-8 (11.93-fold, p<0.05); MMP-9 (10.81-fold, p<0.005); and IL-1β (10.35-fold, p<0.05). For these proteins, greater-fold protein changes were detected in the epidermis compared to dermis. Immunohistochemical analysis confirmed that neutrophils are the predominant cell type in psoriatic skin lesions that express MPO, MMP-8 and MMP-9, and that secukinumab treatment dramatically decreases neutrophil accumulation. Thus, tape stripping may be used to assess epidermal neutrophils, and protein biomarker responses to anti-IL-17A therapy in psoriasis.